Folic acid may be reduced to 5,6,7,8-tetrahydrofolic acid (hereinafter abbreviated as THF) either by catalytic hydrogenation or through the use of NaBH.sub.4. See, for example, CH PS 635 344 for a summary.
THF is the starting material for the preparation of N(5)-formyl-THF, known as folinic acid or leucovorin, and of N(5)-methyl-THF. These two compounds have a great pharmacological usefulness as vitaminic preparations and as rescue agents in cancer chemotherapy. See, for example, EP 0 409 125.
The reduction of folic acid by catalytic hydrogenation, or through the use of NaBH.sub.4, however, produces strongly contaminated THF, which, due to its inherent instability, may not be purified.
The conventional reduction of folic acid with NaBH.sub.4 also requires a considerable excess of NaBH.sub.4 (5 to 30 mole per mole folic acid). This reduction runs only at elevated temperatures (60.degree. C. to 80.degree. C.).
Unpurified THF may be further processed to N(5)-formyl-THF or N(5)-methyl-THF through the use of complicated processes. See CH PS 635 344.
An improved NaBH.sub.4 reduction of folic acid is described in TC. Temple et al., J. Med. Chem. (1979), 22, 731. This reduction runs at room temperature, but still requires a considerable excess of NaBH.sub.4 (about 10 mole per mole folic acid). Due to this considerable excess of NaBH.sub.4, the industrial scale reduction of folic acid by this method does not make sense. Safety concerns due to the danger of explosion also make this method less attractive.
EP 0 608 002 further discloses the reduction of 1 mole folic acid with about 10 mole NaBH.sub.4.
Metal catalyzed NaBH.sub.4 reductions of various substrates, such as ketones, esters, acyl halides, aromatic systems, etc., are known. See Sodium Borchydride Digest, (1995), 3rd ed., Morton International Inc. Catalysts such as Cu(II), Ni(II), Co(II), and lanthanide-salts are used in these NaBH.sub.4 reductions.